Hypoglycemic agent

ABSTRACT

A hypoglycemic agent comprising a compound selected from the group consisting of 24-alkylcholestan-3-ones and 24-alkylcholesten-3-ones (for example, 24-alkylcholestan-3-ones, 24-alkylcholestmonoen-3-ones, 24-alkylcholestdien-3-ones, 24-alkylcholesttrien-3-ones, or 24-alkylcholesttetraen-3-ones, preferably 5-campesten-3-one) as an active ingredient. The agent can be used for improvement of hyperglycemia resulting from diseases such as diabetes, and can be used as a safe medicament without side effects such as hypoglycemia or diarrhea.

TECHNICAL FIELD

The present invention relates to a hypoglycemic agent which is usefulfor therapeutic treatment of diabetes.

BACKGROUND ART

Diabetes is a metabolic abnormality of sugars, proteins, and lipidsresulting from insufficient secretion and activity of insulin. A patientwith the disease will develop symptoms such as polyposia, polyuria, andweight loss, and if the disease is prolonged chronically, severdysfunctions such as retinopathy, nephropathy, neuropathy, myocardialinfarction, and cerebral infarction will arise. The number of patientswith diabetes tends to be increasing all over the world. In our country,the number reached to millions in the 1990s, and a ratio has become asmuch as 5 to 10% of adults over the age of 40. Among the patients,patients with Type-1 (insulin dependent) diabetes are not more than 3%based on the total patient, which diabetes is frequently caused in 25 orless-year-old youths due to extreme deficiency or cease of insulinsecretion. Most of the patients are those with Type-2 (non insulindependent) diabetes resulting from insufficient secretion and activityof insulin.

The cause of type-2 diabetes is not attributable to a single factor. Itis considered that relative deficiency of insulin and lowering of itspotency (insulin resistance) are generated by an inheritedpredisposition and additionally by environmental factors such asovereating, obesity, and underexercise, and as a result, hyperglycemia,ketosis, and hyperlipidemia are caused to develop diabetes.Hyperglycemia is not only a resultant symptom but a cause of furtheraggravation of diabetes (glucose toxicity). Further, on the basis ofrecent studies, an increase of free fatty acid in blood is alsoconsidered as a cause of an aggravation (fat toxicity). However, recentinvestigation in our country revealed that a ratio of Type-2 diabeteswhich accompanies no obesity or hyperlipidemia is about 30%, and a trueetiogenic mechanism has not yet been clarified (Ryo-ya Ueda et al.,Himan-Kenkyu (Journal of Japan Society for the Study of Obesity), Vol.6(No.3), pp. 4-7, 2000).

For treatment of Type-2 diabetes, insulin preparations and oralhypoglycemic agents are used. Among them, insulin preparations are usedfor patients with complications of hyperglycemia or ketosis. However,the preparations are administered by injections, and therefore,determinations of doses and frequency of administration are difficult.Examples of the oral hypoglycemic agents generally used for treatment ofType-2 diabetes include sulfonylurea-type agents, thiazolidinederivative-type agents, biguanide-type agents, and α-glucosidaseinhibitors. Among them, the sulfonylurea-type agents have a risk ofcausing hypoglycemia, the thiazolidine derivative-type agents have arisk of hepatic disorder, the biguanide-type agents have a risk oflactic acidosis, and the α-glucosidase inhibitors often causes sideeffects on the digestive tract. Further, these agents are directed tolowering of blood glucose, and these agents, except the thiazolidinederivative-type agents, have no lowering effect on free fatty acid inblood which is considered as another cause of the disease. Accordingly,these available agents are not satisfactory medicaments from viewpointsof a route of administration, side effects, and efficacy, and amedicament has been desired which has a reduced side effect and is safeand easily administered.

24-Alkylcholestan-3-ones and 24-alkylcholesten-3-ones are known to beuseful as antiobesity agents and agents for improvement of lipidmetabolism (Japanese Patent Unexamined Publication (KOKAI) No.(Hei)11-193296). The above publication discloses that the aforementionedcompounds can be applied to diseases with abnormal lipid metabolism, andthat the diseases with abnormal lipid metabolism includesarteriosclerosis, hypertension, diabetes, and gout, as well ashyperlipidemia or fatty liver resulting from the abnormality of lipidmetabolism (column 16 of the patent publication). However, the abovepublication neither teaches nor suggests that the aforementionedcompounds have hypoglycemic action.

DISCLOSURE OF INVENTION

An object of the present invention is to provide a highly safehypoglycemic agent useful for treatment of diabetes. In particular, theobject of the present invention is to provide a hypoglycemic agent thatsuccessfully exerts hypoglycemic action in Type-2 diabetes which doesnot always accompany obesity and abnormality of lipid metabolism. Theinventors of the present invention conducted various studies to achievethe foregoing object, and as a result, they found that24-Alkylcholestan-3-ones and 24-alkylcholesten-3-ones had remarkablehypoglycemic action and the compound were free from side effects such ashypoglycemia or diarrhea. The present invention was achieved on thebasis of these findings.

The present invention thus provides a hypoglycemic agent comprising acompound selected from the group consisting of 24-alkylcholestan-3-onesand 24-alkylcholesten-3-ones as an active ingredient. According topreferred embodiments of the present invention, provided are theaforementioned hypoglycemic agent, wherein the compound is selected fromthe group consisting of 24-alkylcholestan-3-ones,24-alkylcholestmonoen-3-ones, 24-alkylcholestdien-3-ones,24-alkylcholesttrien-3-ones, and 24-alkylcholesttetraen-3-ones.

According to further preferred embodiments, provided are theaforementioned hypoglycemic agent, wherein the compound is representedby the following general formula (I):

wherein R¹ represents a lower alkyl group; R² represents hydrogen atom,a halogen atom, hydroxy group, or oxo group; and said compound may have1 to 4 double bonds at 1, 4, 5, 6, 7, 8, 8(14), 9(11), 11, 14, 15, 16,22, 23, 24, 25 and/or 25(27)-position(s); and the aforementionedhypoglycemic agent, wherein the compound is 5-campesten-3-one. Thehypoglycemic agents of the present invention can be used for improvementof hyperglycemia in diabetes, and preferably, the agents can be used forimprovement of hyperglycemia in Type-2 diabetes. The hypoglycemic agentsof the present invention also have a lowering effect on urosaccharide,and accordingly, the agents can be used to lower urinary saccharide aswell as to lower blood sugar.

According to further aspects of the present invention, provided are amethod for improvement of hyperglycemia of a mammal including human,which comprises the step of administering an effective amount of acompound selected from the group consisting of 24-alkylcholestan-3-onesand 24-alkylcholesten-3-ones to said mammal. According to a preferredembodiment of said method, the method wherein the hyperglycemia isresulting from Type-2 diabetes is provided.

BRIEF EXPLANATION OF DRAWINGS

FIG. 1 shows changes of a blood sugar level of each group of animals intest example.

FIG. 2 shows results of oral glucose tolerance test (OGTT) applied toeach group of animals (19-week old) in test example.

FIG. 3 shows body weights of each group of animals in test example.

BEST MODE FOR CARRYING OUT THE INVENTION

The active ingredient of the hypoglycemic agent of the present inventionis selected from the group consisting of 24-alkylcholestan-3-ones and24-alkylcholesten-3-ones. Although the number of double bonds containedin the 24-alkylcholesten-3-ones is not particularly limited, 1 to 4double bonds may be preferred. Preferred compounds are selected from thegroup consisting of 24-alkylcholestmonoen-3-ones,24-alkylcholestdien-3-ones, 24-alkylcholesttrien-3-ones, and24-alkylcholesttetraen-3-ones. More preferred compounds may contain 1 to3, more preferably 1 or 2 double bonds at an arbitrary position orpositions. The number of double bonds present in the rings maypreferably be 1 to 3, more preferably 1 or 2, and they may be conjugatedwhen two or more double bonds are present.

More specifically, 24-alkylcholest-4-en-3-ones,24-alkylcholest-5-en-3-ones, 24-alkylcholest-6-en-3-ones,24-alkylcholest-7-en-3-ones, 24-alkylcholest-8-en-3-ones,24-alkylcholest-8(14)-en-3-ones, 24-alkylcholest-9(11)-en-3-ones,24-alkylcholest-14-en-3-ones, 24-alkylcholest-4,6-dien-3-ones,24-alkylcholest-5,7-dien-3-ones, 24-alkylcholest-5,8-dien-3-ones,24-alkylcholest-5,9(11)-dien-3-ones, 24-alkylcholest-8,14-dien-3-ones,24-alkylcholest-1,4,6-trien-3-ones, 24-alkylcholest-4,22-dien-3-ones,24-alkylcholest-5,22-dien-3-ones, 24-alkylcholest-7,22-dien-3-ones,24-alkylcholest-8,22-dien-3-ones, 24-alkylcholest-8(14),22-dien-3-ones,24-alkylcholest-9(11),22-dien-3-ones, 24-alkylcholest-14,22-dien-3-ones,24-alkylcholest-4,6,22-trien-3-ones,24-alkylcholest-5,7,22-trien-3-ones,24-alkylcholest-5,8,22-trien-3-ones,24-alkylcholest-5,9(11),22-trien-3-ones,24-alkylcholest-8,14,22-trien-3-ones,24-alkylcholest-1,4,6,22-tetraen-3-ones,24-alkylcholest-5,25(27)-dien-3-ones,24-alkylcholest-7,16,25-trien-3-ones, 24-alkylcholest-8,24-dien-3-ones,24-alkylcholest-9(11),24-dien-3-ones, 5β-24-alkylcholestan-3-ones andthe like may be used.

The compounds of the aforementioned formula (I) may be used as furtherpreferred compounds. In the formula (I), R¹ represents a lower alkylgroup. As the lower alkyl group, for example, a straight or branchedchain alkyl having 1 to 4, preferably 1 to 3 carbon atoms may be used.For example, methyl group, ethyl group, n-propyl group, isopropyl groupand other may be used. Among them, methyl group or ethyl group ispreferred, and methyl group is particularly preferred. R² representshydrogen atom, a halogen atom, hydroxy group, or oxo group (═O). As thehalogen atom, any of fluorine atom, chlorine atom, bromine atom, andiodine atom may be used. Bromine atom may preferably be used.

In the above formula (I), 1 to 4 double bonds may be present at aposition or positions of 1, 4, 5, 6, 7, 8, 8(14), 9(11), 11, 14, 15, 16,22, 23, 24, 25 and/or 25(27). However, it is readily apparent to thoseskilled in the art that double bonds are not present at adjacentpositions and that, when a double bond is present between the carbonatoms of 5- and 6-positions, a double bond cannot be present between 4-and 5-positions or between 6- and 7-positions. Among them, the bondbetween 5- and 6-positions may preferably be a double bond. Thecompounds wherein the bond between 5- and 6-positions is a double bondand the other bonds are single bonds may be more preferred, and thecompounds wherein the bond between 5- and 6-position is a double bond,R² is hydrogen atom, and the other bonds are single bonds may further bepreferred. Most preferred compounds are those wherein R¹ is methyl groupor ethyl group, R² is hydrogen atom, the bond between 5- and 6-positionsis a double bond, and the other bonds are single bonds.

One or more asymmetric carbon atoms are present in the24-alkylcholestan-3-ones and 24-alkylcholesten-3-ones. Configuration ofeach asymmetric carbon atom is not particularly limited, and the atommay be in either S- or R-configuration (occasionally referred to as α-or β-position). As to the carbon atoms in the formula (I) whoseconfiguration is explicitly shown, it is preferred that each of theatoms is in the configuration as indicated. Examples of particularlypreferred active ingredient of the hypoglycemic agent of the presentinvention include 5-sitosten-3-one (24-ethylcholest-5-en-3-one) and5-campesten-3-one (24-methylcholest-5-en-3-one), and an example of mostpreferred active ingredient includes 5-campesten-3-one. However, theactive ingredients of the hypoglycemic agent of the present inventionare not limited to these compounds.

24-Alkylcholestan-3-ones and 24-alkylcholesten-3-ones can be readilyprepared by those skilled in the art according to known methods forpreparation of cholestan-3-one, cholesten-3-one and the like. Forexample, the preparation of 5-sitosten-3-one, a typical compound thatfalls within the compounds represented by the formula (I), isspecifically explained in the paper by Parish (Parish, E. J., et al.,Synthetic Communications, 22(19), pp. 2839-2847, 1992). The compound canalso be readily prepared by the method of Cheng (Cheng, Y. S., et al.,Synthesis 1980, 223) by using β-sitosterol as a starting material.5-Campesten-3-one can be synthesized from campesterol according to themethod of Shimizu et al. (Japanese Patent Unexamined Publication (KOKAI)No. (Hei)11-295889). Accordingly, it can be readily understood by thoseskilled in the art that 24-alkylcholestan-3-ones and24-alkylcholesten-3-ones can be prepared according to the methodsdescribed in the above publications, or by referring to these methodsand appropriately modifying or altering reaction conditions, reagentsand the like, if required. Methods for preparing24-alkylcholestan-3-ones and 24-alkylcholesten-3-ones, preferably thecompounds represented by the formula (I), are not limited to chemicalsynthetic method, and they can be prepared by biological processes,e.g., culturing microorganisms and the like, or by using enzymesderiving from microorganisms.

The hypoglycemic agent of the present invention is characterized tocomprise one or more compounds selected from the group consisting of24-alkylcholestan-3-ones and 24-alkylcholesten-3-ones, and can be usedas agents for reducing blood sugar. The hypoglycemic agent of thepresent invention can be applied to pathological conditions such asdiabetes wherein hyperglycemia is observed, and the agent has an actionof rapidly improving hyperglycemic conditions to reduce blood sugar to anormal level. Causes of hyperglycemic pathological conditions, to whichthe hypoglycemic agents of the present invention are applicable, are notparticularly limited. Examples of the causes of hyperglycemia includediabetes, as well as side effects of medicaments (for example,adrenocortical hormones, β-blockers, hypotensive diuretics, calciumantagonists and the like), pancreatic failures, chromic hepaticdiseases, endocrine diseases, intracranial hypertensions, obesity,bulimia, alcohol crapula, alimentary hyperglycemia after gastrectomy,pyretogenous diseases such as infectious diseases, carbon monoxidepoisoning, and acute stresses (such as cardiac infarction, cerebralthrombosis and the like). A preferred example of a disease to beapplicable by the hypoglycemic agents of the present invention includesdiabetes-induced hyperglycemic pathological condition. A particularlypreferred example of an applicable disease includes Type-2diabetes-induced hyperglycemia.

As the hypoglycemic agent of the present invention, a compound selectedfrom the group consisting of 24-alkylcholestan-3-ones and24-alkylcholesten-3-ones, per se, may be used. However, it is generallypreferred to use a pharmaceutical composition which is prepared by usingpharmaceutically acceptable additives. The hypoglycemic agent of thepresent invention can be administered orally or parenterally. Examplesof the pharmaceutical compositions suitable for oral administrationsinclude, for example, tablets, granules, capsules, powders, solutions,suspensions, syrups and the like. Examples of the pharmaceuticalcompositions suitable for parenteral administrations include, forexample, injections, drip infusions, suppositories, transdermalpreparations and the like. However, dosage forms of the hypoglycemicagents of the present invention are not limited to these examples. Dosesof the hypoglycemic agents of the present invention should beappropriately increased or decreased depending on the age, conditionsand the like of a patient, the route of administration and otherfactors. Generally, the dose may be within the range of 1 to 5,000 mgper day for an adult.

Pharmaceutical additives used for the preparation of the hypoglycemicagent of the present invention are not particularly limited, and theycan be suitably chosen by those skilled in the art. For example,excipients, binders, lubricants, dispersing agents, suspending agents,emulsifiers, buffering agents, antioxidants, antiseptics, isotonicagents, pH modifiers, solubilizing agents, stabilizers and the like canbe used. Substances used for each of the aforementioned purposes arewell known to those skilled in the art. The active ingredient of thehypoglycemic agent of the present invention, i.e., a compound selectedfrom the group consisting of 24-alkylcholestan-3-ones and24-alkylcholesten-3-ones, is lipophilic. Therefore, the activeingredient can be dissolved in an oily mediums, for example, naturaledible oils such as sesame oil, soybean oil, corn oil, olive oil, cottonseed oil, middle chain fatty acid triglycerides such as Panacete and thelike, and then administered orally. For the above administration, anoily solution containing the active ingredient may preferably beencapsulated in capsules and administered orally, and such means arewell known to those skilled in the art and ordinarily used.

EXAMPLES

The present invention will be more specifically explained with referenceto the following examples. However, the scope of the present inventionis not limited to these examples.

A. Experimental Methods

(1) Materials for Experiments

5-Campesten-3-one was prepared as 24-alkylcholesten-3-one.5-Campesten-3-one was prepared by the method of Shimizu et al. (TakeshiShimizu et al., Method for synthesis of steroids: Japanese PatentUnexamined Publication (KOKAI) No.(Hei) 11-205889) using campesterol asa starting material (purity not less than 98%, Tama Biochemical Co.,Ltd.).

(2) Experimental Animal and Condition for Bleeding

6-Week old c57BL db/db male mice, as being a Type-2 diabetes modelanimal having homozygote diabetes pathogenic gene (db), were divided inthree groups each consisting of 10 animals. A group of healthy c57BLdb/+m male mice (10 animals) having heterozygote db gene was used as acontrol group. The animals were housed in plastic cages for mice at fiveanimals per cage. The animals were fed under feeding conditions at atemperature of 24±1° C. and a relative humidity of 55±5%, where lightand darkness were controlled to change every 12 hours, and each cage andbedding materials were exchanged twice a week. The animals were allowedto water ad libitum.

(3) Experimental Feed

Feed CMF for mouse (Oriental Yeast Co.) was used as a basic feed, and0.1% or 0.3% of 5-campesten-3-one was mixed to the feed to prepare anexperimental feed. The resulting feeds were kept at 4° C. before thestart of feeding.

(4) Experimental Group

The following four experimental groups were arranged and the groups wereobserved for three months.

-   First group: Control group 1 (db/+m, healthy mice)-   Second group: Control group 2 (db/db, mice with Type-2 diabetes)-   Third group: Drug administration group 1 (db/db, the feed    supplemented with 0.1% 5-campesten-3-one)-   Fourth group: Drug administration group 2 (db/db, the feed    supplemented with 0.3% 5-campesten-3-one)

The mice of the first and fourth group were allowed to feed ad libitum,and the mice of the second and third group were fed under the pairfeeding method with the amount of feed consistent with that of thefourth group.

(5) Method for Measurement

Measurements of body weights were carried out with passage of time.Bloods were collected from orbital venous plexus every two weeks fromthe animals, those from 7-week old to 17-week old allowed to feed andwater ad libitum, by using a capillary glass in the period of from 10 to12 a.m., and blood sugar levels were measured by usingGlucoase-CII-Test-Wako (Wako Pure Chemicals Industries Co., Ltd.). Asfor urinary properties, urinary sugar was measured by using a urinarytest paper (Uriace-TB, Terumo Co., Ltd.) and one plus (+) or higherresults were judged as positive.

For oral glucose tolerance test, the animals, starved for 16 hours fromthe night before of the end of the feeding (19-week old), were orallyadministered with glucose (2 g/kg), and the bloods were collected fromorbital venous plexus at time 0 and after 60 and 120 minutes by using acapillary glass to measure blood sugar levels.

The animals were observed every day, and after the end of the feeding(19-week old), the animals were anesthetized to death with carbondioxide gas, and bloods were collected from the abdominal lower venacava and serums were separated. The animals were autopsied, and thebrain, lungs, heart, liver, spleen, pancreas, kidneys, adrenals, andtestis were macroscopically examined and weighed.

Triglycerides, total cholesterol, phospholipids, and free fats weremeasured by using Triglyceride-E-Test Wako, Cholesterol-E-Test Wako,Phospholipid-C-Test Wako, and NEFA-C-Test Wako, respectively. Meanvalues and standard errors for each groups were calculated on the basisof the values measured, and significant differences were determined byt-test.

B. Experimental Results,

(1) Change in Blood Sugar Level

For each groups, changes with time in blood sugar levels are shown inFIG. 1. The blood sugar level of the first group consisting of healthyanimals was changing in a level within 130 to 160 mg/dl. Whilst, thesecond group as being model animals of Type-2 diabetes gave linearincrease from 270 mg/dl (7-week old) to 720 mg/dl (17 week old). Theforth group, as being the model animals of Type-2 diabetes administeredwith 5-campesten-3-one mixed at 0.3% in the feed, gave a almost constantlevel without a significant increase from the initial value of 270 mg/dl(7-week old), and also gave significantly lower values at everymeasuring times after 9-week old as compared to the levels of thecontrol group (the second group). In the third group administered with5-campesten-3-one mixed at 0.1% in the feed, it was observed that theblood sugar level was increased and decreased in 9-week old and 11-weekold, respectively, relative to the control group (the second group), andthen became a lower level in 17-week old.

(2) Oral Glucose Tolerance Test (OGTT)

The results of OGTT were shown in FIG. 2. The curve of blood sugar levelof the second group was 654 mg/dl at time 0, 802 mg/dl at 60 minutes,and 655 mg/dl at 120 minutes, which were remarkably high values ascompared to the levels of the healthy mouse (the first group). Whist,the third group gave 497 mg/dl at time 0, 703 mg/dl at 60 minutes, and558 mg/dl at 120 minutes, which were significantly lower than the levelsof the second group at every measuring points. The fourth group gave 282mg/dl as the value of time 0, which is lower than the half of the levelof the second group, and gave almost the same 60-munites value as thatof the third group. However, the group gave 440 mg/dl as a 120-minutesvalue which was lower than that of the third group.

(3) Urinary Sugar

As shown in Table 1, in the group of healthy mice (the first group), allof the mice gave negative results during the test period, except onemouse of 17-week old gave a positive result (10%). Whilst as for urinarysugar of the second group consisting of the mice with Type-2 diabetes,the mice gave a positive ratio of 56% in 7-week old, and all mice gavepositive results in 9-week old (100%), which 100% positive rate wasmaintained during the whole period afterwards. In addition, almost thewhole mice in the group gave three plus or more (+++, 2,000 mg/dl) asresults of urinary concentrations. As for the urinary sugar in the thirdgroup administered with 5-campesten-3-one mixed at 0.1% in the feed, themice gave a positive ratio of 63% in 7-week old and then 100% in 13-weekold, and each of all the mice, a delay in giving a positive result wasobserved. In the forth group administered with 5-campesten-3-one mixedat 0.3% in the feed, a positive ratio of urinary sugar was found to beincreased or decreased in a range of 14 to 70%, however, the group didnot give entirely positive results. As for positive degrees of urinarysugar in this group, almost a half of the mice gave one plus (+, 150mg/dl) or two plus (++, 500 mg/dl), which was lower than the results ofthe control group (the second group).

Control Group 1 (db/+m) Period Number Week (week) of mice − ± + ++ +++Positive ratio 7 0 10 10 0 0 0 0 0 9 2 7 7 0 0 0 0 0 11 4 10 10 0 0 0 00 13 6 9 9 0 0 0 0 0 15 8 10 9 1 0 0 0 0 17 10 10 9 0 1 0 0 10

Control Group 2 (db/db) Period Number Week (week) of mice − ± + ++ +++Positive ratio 7 0 9 4 0 1 1 3 56 9 2 8 0 0 2 2 4 100 11 4 10 0 0 0 0 10100 13 6 10 0 0 1 0 9 100 15 8 10 0 0 0 0 10 100 17 10 10 0 0 0 0 10 100

Drug Administration Group 1 (db/db, Mixed at 0.1% in the Feed) PeriodNumber Week (week) of mice − ± + ++ +++ Positive ratio 7 0 8 2 1 1 0 463 9 2 7 1 2 0 2 2 57 11 4 9 1 0 1 0 7 89 13 6 9 0 0 0 0 9 100 15 8 9 00 0 1 8 100 17 10 9 0 0 1 0 8 100

Drug Administration Group 2 (db/db, Mixed at 0.3% in the Feed) PeriodNumber Week (week) of mice − ± + ++ +++ Positive ratio 7 0 7 6 0 0 0 114 9 2 5 4 0 0 1 0 20 11 4 8 2 1 0 2 3 63 13 6 10 5 0 1 2 2 50 15 8 9 41 1 1 2 44 17 10 10 1 2 3 1 3 70(4) Body Weight

As for the body weights of the mice of 19-week old, obesity was observedin the model mice with Type-2 diabetes as compared to the healthy mice(the first group) as shown in FIG. 3. The body weight of the groupadministered with 5-campesten-3-one mixed at 0.3% in the feed (the forthgroup) was significantly higher than that of the control group (thesecond group). The results can be interpreted that, in the same mannerof the action of the thiazolidine derivative-type drug as being otherdrug for treatment of diabetes, the insulin resistance was improved by5-campesten-3-one, and as a result, an accumulation of body fat byinsulin was enhanced.

(5) Autopsical Finding

In autopsy of the brain, heart, lungs, livers, pancreas, spleen,kidneys, and adrenals, no particular abnormality was observed, exceptthat some of the mice with Type-2 diabetes (the second group, the thirdgroup, and the forth group) were found to exhibit the conditions of fatliver. The mice with Type-2 diabetes were found to be in copulativeimpotence, and the weights of their testis were as low as 50 to 60% ascompared to that of the healthy mice (the first group). Whilst, theweight of the testis (absolute weight) of the group administered with5-campesten-3-one mixed at 0.3% in the feed (the forth group) was foundto be 85% of that of the healthy mice (the first group).

(6) General Conditions

As for the general conditions of each of the groups during theexperimental period, no particular abnormality was observed, exceptdifferences in body weights, and no abnormal findings such as diarrheawas observed. A tendency of polyuria was observed in the mice withType-2 diabetes as compared to the healthy mice (the first group).

INDUSTRIAL APPLICABILITY

The hypoglycemic agent of the present invention can be used forimprovement of hyperglycemia resulting from diseases such as diabetes,and can be used as a safe medicament without side effects such ashypoglycemia or diarrhea.

1. (canceled)
 2. (canceled)
 3. (canceled)
 4. A hypoglycemic agentcomprising 5-campesten-3-one as an active ingredient.
 5. Thehypoglycemic agent according to claim 4, which is used for improvementof hyperglycemia resulting from Type-2 diabetes.